One of the most prevalent forms of hormone therapy today is that of estrogen replacement therapy in women. Estrogen therapy is prescribed widely not only for the alleviation of menopausal symptoms but also for the prevention of osteoporosis and cardiovascular disease. Furthermore, estrogen may have utility as a therapeutic treatment for chronic neurodegenerative diseases such as Alzheimer's disease.
Estrogen therapy is still very much a "hit-or-miss" treatment. Doses are increased for a patient until symptoms are observed to subside. Some women respond to this approach and others do not. In addition, the treatment protocol may be adversely affected by transient side effects which can be short term (such as nausea or bloating) or long term (such as increased susceptibility to cancer). There is no way to predict, in advance, whether a woman will respond in the long term to estrogen therapy; whether alternative versions of the drug will work better; or whether life-long therapy is for naught.
Numerous studies on the treatment of menopause with estrogen have revealed a dramatic biological variability in response to a common event--the 95% or greater decline in ovarian estradiol (E.sub.2 .beta.) at the menopause. The interpersonal variability in symptoms that is a hallmark of the decline in estrogen levels during menopause is also manifest in the response of individuals to estrogen replacement therapy. Seventy five to 80% of women undergoing the natural menopause, and 95-100% of oophorectomized women experience physiological and/or psychological problems associated with the decline of steroids (Utian (1977), Obstet. Gynecol. Survey 32:193-97). Twenty to 25% of women are unaffected (Haenngi et al. (1993), Maturitas 16:111-122), the remainder of women have symptoms that exhibit a wide variance. These symptoms include hot flushes, perspiration, muscle and joint pain, fatigue, headaches and irritability and vary greatly in both their intensity and frequency (Utian (1977)). Hot flushes, the cardinal sign of the menopause, persist for more than one year in 95% of affected women (Jaszmann et al. (1969), Med. Gynecol. Sociol. 4:268-277; McKinlay et al. (1974), Br. J. Prev. Soc. Med. 28:108-111). Some women experience as few as one flush per month while others have one flush per hour (Jaszman et al. (1969), McKinley et al. (1974)). Menopausal hot flushes can also vary in severity and/or impact from not bothersome to totally incapacitating--in some cases preventing afflicted women from working. Treatment of these menopausal symptoms by estrogen replacement therapy has proved to be effective for some individuals and not for others.
When estrogen replacement therapy is prescribed for additional conditions associated with decline of naturally occurring estrogen including osteoporosis and cardiovascular disease, women may be put on therapy for 20 years or more, not knowing whether the treatment will be effective in preventing these conditions. The uncertainty associated with the outcome of long term estrogen replacement therapy results in unnecessary health care costs; postponement of the use of alternative treatments that might benefit the patient during the time when estrogen therapy is being administered to the unresponsive patient and a certain risk of side effects such as increased susceptibility to breast and endometrial cancers, hypertension and gall bladder disease with no actual benefit to offset the risk for the patient. Furthermore, women who respond well to estrogen may be able to benefit from a reduced dose of estrogen. There are many types of estrogens on the market and many more in research and development. It is possible that one type of estrogen may be better suited to an individual's needs than another. A test that could predict or determine the responsiveness of a patient to estrogen therapy would have utility in therapy planning by reducing the uncertainty now associated with the outcome of longterm estrogen replacement therapy. Such a test would make hormone replacement therapy available to an increased number of women with concomitant overall reduction in morbidity associated with frailty and cardiovascular disease. No test is currently available that measures the responsiveness of an individual to estrogen therapy nor predicts in advance, responsiveness to estrogen therapy.
In some circumstances, estrogen therapy is not recommended regardless of its potential efficacy. For example, in the case of women suffering from breast cancer or for men, hormone replacement therapy using a hormone other than estrogen is desirable for inhibiting hot flushes as well as other symptoms of menopause. An example of such a hormone is megastrol acetate. This hormone which is a progestational agent, has also been found to inhibit hot flushes in androgen deficient males without encountering the adverse side effects seen with estrogen. Other examples of progestational agents are medroxyprogesterone and d-norgestrol. Non-steroidal medications such as dithiocarbomyl hydrazine and clonidine have been found to be partially effective while propanolol, vitamin E, K, mineral supplements, belladonna alkaloids, in combination with mild sedatives, tranquilizers and antidepressants have all been used for relief of hot flushes but their effectiveness has not been critically evaluated (Judd, 1983, Neuroendocrinology of Aging, J. Meites ed., New York: Plenum Press).
As exemplified by estrogen, hormone replacement is a long-term treatment. A method of determining in advance whether hormone treatment could be effective would have utility both in saving medical costs and in avoiding unnecessary adverse side effects associated with the use of these molecules.
Accordingly, a need exists for a method for determining or predicting the responsiveness of individuals to hormone therapy.